This application is for renewed funding for yrs 21 to 25 of RO1 AR27065 "Epidemiology of Age-Related Bone Loss and Fractures." Osteoporosis accounts for at least 1.5 million fractures and costs $14 billion annually in the United States. We will continue our population-based studies on risk factors for osteoporosis using conventional methodologies and the infrastructure of the Rochester Epidemiology Project. However, we will also employ, for the first time in an epidemiologic study, two new state- of-the-art technologies--spiral volumetric quantitative computed tomography (QCT) of the spine and hips (CV 0.7-0.9%) and ultra-high resolution, 3-dimensional peripheral QCT (CV equal to or < 0.4%) of the distal radius and tibia. These instruments allow quantitative measurement of bone macrostructure, such as shape and size, separate determination of cancellous and cortical volumetric bone mineral density (BMD), and assessment of bone microstructural characteristics, such as cortical porosity and trabecular connectivity ("noninvasive bone biopsy"). The proposed research will extend followup on two age-stratified cohorts of Rochester, MN residents (304 women enrolled approximately 1980 and 351 women and 348 men enrolled approximately 1990) but most studies will be made in a new age-stratified cohort of 350 Rochester women and 350 men. Our Specific Aims are: 1) to validate a nationally-employed fracture prediction model; 2) to define the age-related, sex-specific changes of bone macro- and microstructure and to use these to test a number of hypotheses related to pathophysiology and to clinical issues; 3) to test the hypotheses that specific measurements of bone macrostructural and microstructural variables will greatly enhance fracture prediction as compared with BMD by dual-energy x-ray absorptiometry; 4) to assess the pathophysiologic mechanisms by which estrogen (E)-deficiency causes bone loss by testing the hypotheses that postmenopausal women with lower levels of E and E-metabolites have greater bone loss, that secondary hyperparathyroidism in late postmenopausal women interacts with E deficiency to protect against cancellous bone loss but to enhance cortical bone loss, and that alterations in levels of serum l,25(OH)2D3 and IGF-I contribute to bone loss in E deficient women; and 5) in aging men, to test the hypotheses that E-deficiency is the main cause of calcellous bone loss and T- deficiency is the main cause of cortical bone loss. The new bone structure measurements should take us to a new level of understanding of the causes of age-related bone loss and fractures and improve substantially the assessment of risk for osteoporosis.